A mathematical model of tumour self-seeding reveals secondary metastatic deposits as drivers of primary tumour growth

Two models of circulating tumour cell (CTC) dynamics have been proposed to explain the phenomenon of tumour ‘self-seeding’, whereby CTCs repopulate the primary tumour and accelerate growth: primary seeding, where cells from a primary tumour shed into the vasculature and return back to the primary themselves; and secondary seeding, where cells from the primary first metastasize into a secondary tissue and form microscopic secondary deposits, which then shed cells into the vasculature returning to the primary. These two models are difficult to distinguish experimentally, yet the differences between them is of great importance to both our understanding of the metastatic process and also for designing methods of intervention. Therefore, we developed a mathematical model to test the relative likelihood of these two phenomena in the subset of tumours whose shed CTCs first encounter the lung capillary bed, and show that secondary seeding is several orders of magnitude more likely than primary seeding. We suggest how this difference could affect tumour evolution, progression and therapy, and propose several possible methods of experimental validation.